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EP0959873B1 - Procedes et composition a base de gel - Google Patents

Procedes et composition a base de gel Download PDF

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Publication number
EP0959873B1
EP0959873B1 EP97952575A EP97952575A EP0959873B1 EP 0959873 B1 EP0959873 B1 EP 0959873B1 EP 97952575 A EP97952575 A EP 97952575A EP 97952575 A EP97952575 A EP 97952575A EP 0959873 B1 EP0959873 B1 EP 0959873B1
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EP
European Patent Office
Prior art keywords
beneficial agent
solvent
benzoate
composition according
gel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP97952575A
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German (de)
English (en)
Other versions
EP0959873A2 (fr
Inventor
Kevin J. Brodbeck
Ann T. Gaynor-Duarte
Theodore T. Shen
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Alza Corp
Original Assignee
Alza Corp
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Publication date
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • the present invention relates to a gel composition that can be implanted into a desired location and which can provide controlled release of a beneficial agent.
  • the present invention also relates to methods of controlling release of a beneficial agent from a composition.
  • Biodegradable polymers have been used for many years in medical applications. Illustrative devices composed of the biodegradable polymers include sutures, surgical clips, staples, implants, and sustained release drug delivery systems. The majority of these biodegradable polymers have been based upon glycolide, lactide, caprolactone, and copolymers thereof.
  • the biodegradable polymers can be thermoplastic materials which means that they can be heated and formed into various shapes such as fibers, clips, staples, pins, films, etc. Alternatively, they can be thermosetting materials formed by crosslinking reactions which lead to high-molecular-weight materials that do not melt or form flowable liquids at high temperatures.
  • thermoplastic and thermosetting biodegradable polymers have many useful biomedical applications, there are several important limitations to their use in the bodies of various animals including humans, animals, birds, fish, and reptiles. Because these polymers generally are solids, all instances involving their use have required initially forming the polymeric structures outside the body, followed by insertion of the solid structure into the body. For example, sutures, clips, and staples are all formed from thermoplastic biodegradable polymers prior to use. When inserted into the body, they retain their original shape. While this characteristic is essential for some uses, it is not preferred where it is desired that the material be molded or flow to fill voids or cavities where it may be most needed.
  • thermoplastic or thermosetting biodegradable polymers also often are or have to be formed outside the body.
  • the drug is incorporated into the polymer and the mixture is shaped into a certain form such as cylinder, disc, or fiber for implantation.
  • the drug delivery system has to be inserted into the body through an incision. These incisions are sometimes larger than desired by the medical profession and occasionally lead to a reluctance of the patient to accept such an implant or drug delivery system. Nonetheless, both biodegradable and non-biodegradable implantable drug delivery systems have been widely used successfully.
  • the device is prepared from a core that is sprayed with a solution having a polymer and a solvent that is composed of a rapidly evaporating, low boiling point first solvent and a slowly evaporating, high boiling point second solvent.
  • illustrative osmotic delivery systems include those disclosed in U.S. Patent Nos. 3,797,492, 3,987,790, 4,008,719, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,151,093, 5,234,692, 5,234,693, 5,279,608, and 5,336,057.
  • Pulsatile delivery devices are also known which deliver a beneficial agent in a pulsatile manner as disclosed in U.S. Patent Nos. 5,209,746, 5,308,348, and 5,456,679.
  • U.S. Patent No. 5,019,400 describes the preparation of controlled release microspheres via a very low temperature casting process. These materials may or may not contain a drug which can be released into the body. Although these materials can be injected into the body with a syringe, they do not always satisfy the demand for a biodegradable implant. Because they are particulate in nature, they do not form a continuous film or solid implant with the structural integrity needed for certain prostheses.
  • microspheres or microcapsules prepared from these polymers and containing drugs for release into the body are sometimes difficult to produce on a large scale, and their storage and injection characteristics present problems.
  • one other major limitation of the microcapsule or small-particle system is their lack of reversibility without extensive surgical intervention. That is, if there are complications after they have been injected, it is considerably more difficult to remove them from the body than with solid implants.
  • a still further limitation on microparticles or microcapsulation is the difficulty in encapsulating protein and DNA-based drugs without degradation caused by denaturing solvents and temperature extremes used during processing.
  • U.S. Patent No. 4,938,763 and its divisional U.S. Patent No. 5,278,201 relate to a biodegradable polymer for use in providing syringeable, in-situ forming, solid biodegradable implants for animals.
  • a thermoplastic system is used wherein a nonreactive polymer is dissolved in a water soluble biocompatible solvent to form a liquid which is placed in the animal wherein the solvent dissipates to produce the solid implant.
  • thermosetting system is used wherein effective amounts of a liquid acrylic ester-terminated, biodegradable prepolymer and a curing agent are formed and the liquid mixture is placed within the animal wherein the prepolymer cures to form the solid implant. It is stated that the systems provide a syringeable, solid biodegradable delivery system by the addition of an effective level of a biologically active agent to the liquid before the injection into the animal.
  • U.S. Patent 5,599,552 describes thermoplastic and thermoset polymer compositions that utilize solvents which are miscible to dispersible in water, such as N-methyl-2-pyrrolidone, resulting in polymer solutions capable of quickly absorbing water from surrounding tissue.
  • the polarity of the solvents is described as being effective to provide about at least 10% solubility in water.
  • the polymer matrix systems are described as forming a porous core surrounded by a porous skin.
  • U.S. Patent No. 5,242,910 describes a sustained release composition containing drugs for treating periodontal disease.
  • the composition comprises copolymers of lactide and glycolide, triacetin (as a solvent/plasticizer) and an agent providing relief of oral cavity diseases.
  • the composition can take the form of a gel and can be inserted into a periodontal cavity via a syringe using either a needle or a catheter.
  • the composition can contain surfactants, flavoring agents, viscosity controlling agents, complexing agents, antioxidants, other polymers, gums, waxes/oils, and coloring agents.
  • One illustrative viscosity controlling agent set forth in one of the examples is polyethylene glycol 400.
  • U.S. Patent No. 5,620,700 describes a polymer-drug matrix, optionally including plasticizers in an amount up to about 30 wt %, for local application of drug in the peridontal cavity.
  • plasticizers listed are, inter alia, triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, diethyl phthalate, diethyl tartrate, ethyl lactate, triacetin and diacetin.
  • the polymer matrix is non-flowable prior to administration and is heated to become flowable so that it may be dispensed into the peridontal cavity where it solidifies. While the patent discusses possible systemic applications by delivery via the ocular sacs of the eye or intravaginal delivery, it does not address the issue of burst of drug or methods of controlling burst.
  • U.S. Patent No. 3,923,939 describes a method of reducing initial burst of an active agent from a delivery device by removing, prior to implantation, active agent from the exterior surface of the delivery device and through a layer of at least 5% of the overall body thickness extending from the exterior surface of the device.
  • U.S. Patent No. 5,556,905 describes degradable thermoplastic compositions which are modified by plasticizers consisting of various partial esters of citric acid.
  • WO 95/27481A discloses a liquid delivery composition for the sustained delivery of an active agent which includes a liquid formulation of a biocompatible polymer or prepolymer in combination with a controlled release component, which includes an active agent.
  • the composition may be introduced into the body of a subject in liquid form, and then solidifies or cures in situ to form a controlled release implant.
  • Prior art polymer compositions for injectable implants have used solvent/plasticizers that are very or relatively soluble in aqueous body fluids to promote rapid solidification of the polymer at the implant site and promote diffusion of drug from the implant.
  • solvent/plasticizers that are very or relatively soluble in aqueous body fluids to promote rapid solidification of the polymer at the implant site and promote diffusion of drug from the implant.
  • a serious problem associated with prior art polymeric implants utilizing water soluble polymer solvents is the rapid migration of water into the polymer composition when the implant is placed in the body and exposed to aqueous body fluids. That characteristic often results in uncontrolled release of beneficial agent that is manifested by an initial, rapid release of beneficial agent from the polymer composition, corresponding to a "burst" of beneficial agent being released from the implant.
  • the burst often results in a substantial portion of the beneficial agent, if not all, being released in a very short time, e.g., hours or 1-2 days. Such an effect can be unacceptable, particularly in those circumstances where sustained delivery is desired, i.e., delivery of beneficial agent over a period of a week or a month or more, or where there is a narrow therapeutic window and release of excess beneficial agent can result in adverse consequences to the subject being treated, or where it is necessary to mimic the naturally-occurring daily profile of beneficial agents, such as hormones and the like, in the body of the subject being treated.
  • solvent-based depot compositions comprised of a polymer dissolved in a solvent
  • another problem which often exists is that the composition solidifies slowly after injection as solvent diffuses from the depot and water migrates into the depot. Since these compositions are relatively non-viscous in order to be injected, a large percentage of drug may be rapidly released as the system forms by diffusion of the solvent, particularly when the beneficial agent is soluble in the solvent and the solvent rapidly disperses into body fluids. Rapid solvent release contributes to the "burst" effect along with depot hardening due to water uptake. In this respect, it is typical for conventional solvent-based compositions to have a drug burst wherein 30-75% of the drug contained in the composition is released within one day of the initial injection.
  • the surface pores take on a finger-like pore structure extending for as much as 1/3 of a millimeter or more from the implant surface into the implant, and such finger-like pores are open at the surface of the implant to the environment of use.
  • the internal pores tend to be smaller and less accessible to the fluids present in the environment of use.
  • the finger-like pores allow very rapid uptake of aqueous body fluids into the interior of the implant with consequent immediate and rapid dissolution of significant quantities of beneficial agent and unimpeded diffusion of beneficial agent into the environment of use, producing the burst effect discussed above.
  • lag time is undesirable from the standpoint of presenting a controlled, sustained release of beneficial agent to the subject being treated.
  • the present invention provides an implantable system for systemic and local delivery of a beneficial agent to a subject.
  • the system provides controlled release of beneficial agent to the subject being treated and limit the initial burst of beneficial agent from the implant system. Additionally, the invention provides a method of preparing implant systems having restricted initial burst of beneficial agent.
  • the invention may be used to administer, locally or systemically, a beneficial agent to a subject by implanting a system comprising a beneficial agent dispersed or dissolved substantially throughout a viscous gel, the system releasing 20% or less by weight of the beneficial agent present in the viscous gel within the first 24 hours after implantation in the subject.
  • a beneficial agent dispersed or dissolved substantially throughout a viscous gel
  • the system releasing 20% or less by weight of the beneficial agent present in the viscous gel within the first 24 hours after implantation in the subject.
  • 10% or less by weight of the beneficial agent will be released within the first 24 hours after implantation.
  • the invention may also be used to systemically administer a beneficial agent to a subject which by implanting a system comprising a beneficial agent dispersed or dissolved substantially throughout a viscous gel, the system having a burst index of 8 or less.
  • the invention may be used to systemically administer a beneficial agent to a subject in a controlled manner approximating zero order release by implanting a gel composition comprising a biocompatible polymer, a biocompatible solvent having a solubility in water of less than 7% and forming a viscous gel with the polymer, and a beneficial agent, wherein the loading of the beneficial agent in the interior of the polymer gel is above that required to saturate the beneficial agent in water.
  • an implantable, biodegradable composition for the sustained delivery of a beneficial agent to a subject
  • the composition comprises a polylactide polymer; an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and a beneficial agent dissolved or dispersed in the gel
  • the solvent comprises a single solvent having a miscibility in water of less than 7% by weight or a mixture of solvents with at least one solvent in the mixture having a miscibility in water of less than 7% by weight wherein the at least one solvent having a miscibility in water of less than 7% by weight is selected from lower alkyl and aralkyl esters of benzoic acid.
  • the miscibility in water of the solvent mixture is 20% or less by weight, and more preferably 10% or less by weight.
  • the solvent is selected from the group comprising compounds having the following structural formula: wherein R 1 is phenyl and R 2 is aralkyl or lower alkyl.
  • composition may optionally include one or more of the following:
  • the solvent may have a miscibility in water of 6% or less by weight, for example 5% or less by weight.
  • an injectable depot gel composition comprising:
  • the beneficial agent may be selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof.
  • the composition preferably has a burst index of less than 8.
  • the invention comprises a kit for administration of a beneficial agent to a subject comprising:
  • the composition may comprise a poly(lactide-co-glycolide) copolymer.
  • the composition may comprise a viscous gel in which the beneficial agent is dispersed or dissolved, wherein the viscous gel maintains a glass transition temperature of less than 37°C for at least the first 24 hours after implantation.
  • the present invention is directed to a composition for administering a beneficial agent to a subject by implanting in the subject an implantable system which may be formed as a viscous gel from a biocompatible polymer and a biocompatible solvent, and a beneficial agent is substantially dissolved or dispersed throughout the gel.
  • an implantable system which may be formed as a viscous gel from a biocompatible polymer and a biocompatible solvent, and a beneficial agent is substantially dissolved or dispersed throughout the gel.
  • the implant systems useful in this invention will release, in the first 24 hours after implantation, 20% or less of the total amount of beneficial agent to be delivered to the subject from the implant system, preferably 15% or less and more preferably 10% or less.
  • the viscous gel formed preferably is bioerodible so that the implant system does not have to be surgically removed after beneficial agent is depleted from the implant.
  • Water uptake and burst may be controlled by using polymer-solvent compositions wherein the solvent is substantially immiscible in water, i.e., less than 7% by weight soluble in water, so as to control the rate of water migration into the polymer implant and ultimately control the burst of beneficial agent and the sustained delivery of beneficial agent.
  • the compositions of the invention will be gel-like and will form with a substantially homogeneous pore structure throughout the implant upon implantation and during drug delivery, even as it hardens.
  • the polymer gel implant will slowly harden when subjected to an aqueous environment, the hardened implant may maintain a rubbery (non-rigid) composition with the glass transition temperature being below 37°C.
  • the viscosity optionally may be modified by emulsifiers to obtain a gel composition having a viscosity low enough to permit passage of the gel composition through a needle.
  • pore formers and solubility modulators of the beneficial agent may be added to the implant systems to provide desired release profiles from the implant systems, along with typical pharmaceutical excipients and other additives that do not change the beneficial aspects of the present invention.
  • the addition of a solubility modulator to the implant system may enable the use of a solvent having a solubility of 7% or greater in the implant system with minimal burst and sustained delivery under particular circumstances.
  • the implant system utilize at least one solvent having a solubility in water of less than 7% by weight, whether the solvent is present alone or as part of a solvent mixture. It has also been discovered that when mixtures of solvents which include a solvent having 7% or less by weight solubility in water and one or more miscible solvents, optionally having greater solubility, are used, implant systems exhibiting limited water uptake and minimal burst and sustained delivery characteristics are obtained.
  • beneficial agent means an agent that effects a desired beneficial, often pharmacological, effect upon administration to a human or an animal, whether alone or in combination with other pharmaceutical excipients or inert ingredients.
  • AUC means the area under the curve obtained from an in vivo assay in a subject by plotting blood plasma concentration of the beneficial agent in the subject against time, as measured from the time of implantation of the composition, to a time " t " after implantation.
  • the time t will correspond to the delivery period of beneficial agent to a subject.
  • burst index means, with respect to a particular composition intended for systemic delivery of a beneficial agent, the quotient formed by dividing (i) the AUC calculated for the first twenty-four hours after implantation of the composition into a subject divided by the number 24, by (ii) the AUC calculated for the time period of delivery of beneficial agent, divided by the number of hours in the total duration of the delivery period.
  • dissolved or dispersed is intended to encompass all means of establishing a presence of beneficial agent in the gel composition and includes dissolution, dispersion, suspension and the like.
  • systemic means, with respect to delivery or administration of a beneficial agent to a subject, that beneficial agent is detectable at a biologically-significant level in the blood plasma of the subject.
  • the term "local” means, with respect to delivery or administration of a beneficial agent to a subject, that beneficial agent is delivered to a localized site in the subject but is not detectable at a biologically-significant level in the blood plasma of the subject.
  • gel vehicle means the composition formed by mixture of the polymer and solvent in the absence of the beneficial agent.
  • sustained period means a period of time over which release of a beneficial agent from the implant of the invention occurs, which will generally be about one week or longer, and preferably about 30 days or longer.
  • initial burst means, with respect to a particular composition of this invention, the quotient obtained by dividing (i) the amount by weight of beneficial agent released from the composition in a predetermined initial period of time after implantation, by (ii) the total amount of beneficial agent that is to be delivered from an implanted composition. It is understood that the initial burst may vary depending on the shape and surface area of the implant. Accordingly, the percentages and burst indices associated with initial burst described herein are intended to apply to compositions tested in a form resulting from dispensing of the composition from a standard syringe.
  • solubility modulator means, with respect to the beneficial agent, an agent that will alter the solubility of the beneficial agent, with reference to polymer solvent or water, from the solubility of beneficial agent in the absence of the modulator.
  • the modulator may enhance or retard the solubility of the beneficial agent in the solvent or water.
  • the solubility modulator will generally be an agent that will retard the solubility of the beneficial agent in water.
  • the effects of solubility modulators of the beneficial agent may result from intereactions of the solubility modulator with the solvent, or with the beneficial agent itself, such as by the formation of complexes, or with both.
  • solubility modulator when the solubility modulator is “associated” with the beneficial agent, all such interactions or formations as may occur are intended. Solubility modulators may be mixed with the beneficial agent prior to its combination with the viscous gel or may be added to the viscous gel prior to the addition of the beneficial agent, as appropriate.
  • subject means, with respect to the administration of a composition of the invention, an animal or a human being.
  • solubility values of solvent in water are considered to be determined at 20°C. Since it is generally recognized that solubility values as reported may not always be conducted at the same conditions, solubility limits recited herein as percent by weight miscible or soluble with water as part of a range or upper limit may not be absolute.
  • solvent solubility in water is recited herein as “7% by weight”, and no further limitations on the solvent are provided, the solvent "triacetin”, which has a reported solubility in water of 7.17 grams in 100 ml of water, is considered to be included within the limit of 7%.
  • a solubility limit in water of less than 7% by weight as used herein does not include the solvent triacetin or solvents having solubilities in water equal to or greater than triacetin.
  • the polymer, solvent and other agents used in the invention must be biocompatible: that is they must not cause irritation or necrosis in the environment of use.
  • the environment of use is a fluid environment and may comprise a subcutaneous or intramuscular portion or body cavity of a human or animal.
  • Polymers that are used in the invention are polylactides.
  • a polylactide is a lactic acid-based polymer that can be based solely on lactic acid or can be a copolymer based on lactic acid and glycolic acid which may include small amounts of other comonomers that do not substantially affect the advantageous results which can be achieved in accordance with the present invention.
  • lactic acid includes the isomers L-lactic acid, D-lactic acid, DL-lactic acid and lactide while the term “glycolic acid” includes glycolide.
  • Most preferred are poly(lactide-co-glycolide)copolymers, commonly referred to as PLGA.
  • the polymer may have a monomer ratio of lactic acid/glycolic acid of from about 100:0 to about 15:85, preferably from about 60:40 to about 75:25 and an especially useful copolymer has a monomer ratio of lactic acid/glycolic acid of about 50:50.
  • the lactic acid-based polymer has a number average molecular weight of from about 1,000 to about 120,000, preferably from about 5,000 to about 30,000 as determined by gas phase chromatography.
  • the polymer can be prepared in accordance with the teachings of U.S. Patent No. 4,443,340.
  • the lactic acid-based polymer can be prepared directly from lactic acid or a mixture of lactic acid and glycolic acid (with or without a further comonomer) in accordance with the techniques set forth in U.S. Patent No. 5,310,865.
  • Suitable lactic acid-based polymers are available commercially. For instance, 50:50 lactic acid:glycolic acid copolymers having molecular weights of 5,000, 10,000, 30,000 and 100,000, preferably about 8,000 to 13,000, and most preferably about 10,000, and a wide variety of end groups to alter susceptibility to hydrolysis and subsequent breakdown of the polymer chain are available from Boehringer Ingelheim (Petersburg, VA).
  • the biocompatible polymer is present in the gel composition in an amount ranging from about 5 to about 80% by weight, preferably from about 30 to about 70% by weight and often 40 to 60% by weight of the viscous gel, the viscous gel comprising the combined amounts of the biocompatible polymer and the solvent.
  • the solvent will be added to polymer in amounts described below, to provide implantable or injectable viscous gels.
  • the solvent must be biocompatible, should form a viscous gel with the polymer, and restrict water uptake into the implant.
  • the solvent may be a single solvent or a mixture of solvents exhibiting the foregoing properties.
  • the solvents are five weight percent or less soluble in water; more preferably three weight percent or less soluble in water; and even more preferably one weight percent or less soluble in water.
  • the solubility of the solvent in water is equal to or less than 0.5 weight percent.
  • Water miscibility may be determined experimentally as follows: Water (1-5 g) is placed in a tared clear container at a controlled temperature, about 20°C, and weighed, and a candidate solvent is added dropwise. The solution is swirled to observe phase separation. When the saturation point appears to be reached, as determined by observation of phase separation, the solution is allowed to stand overnight and is re-checked the following day. If the solution is still saturated, as determined by observation of phase separation, then the percent (w/w) of solvent added is determined. Otherwise more solvent is added and the process repeated. Solubility or miscibility is determined by dividing the total weight of solvent added by the final weight of the solvent/water mixture. When solvent mixtures are used, for example 20% triacetin and 80% benzyl benzoate, they are pre-mixed prior to adding to the water.
  • Solvents useful in this invention are generally less than 7% water soluble by weight as described above, and are selected from the lower alkyl and aralkyl esters of benzoic acid.
  • the solvents are those having solubilities within the foregoing range selected from (i) compounds having the following structural formulas : in which R 1 is phenyl and R 2 is lower alkyl or aralkyl.
  • lower alkyl means straight or branched chain hydrocarbons having 1-6 carbon atoms, optionally substituted with non-interfering substituents
  • aralkyl means (lower alkyl)phenyl, e.g., benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, and the like wherein the alkyl moiety contains from 1-6 carbon atoms.
  • solvents useful in the invention are available commercially (Aldrich Chemicals, Sigma Chemicals) or may be prepared by conventional esterification of benzoic acid using acid halides, and optionally esterification catalysts, such as described in US Patent No. 5,556,905.
  • Art recognized benzoic acid derivatives from which solvents having the requisite solubility may be selected include: 1,4-cyclohexane dimethanol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol benzoate and dipropylene glycol benzoate blend, Polyethylene glycol (200) dibenzoate, iso decyl benzoate, neopentyl glycol dibenzoate, glyceryl tribenzoate, pentaerylthritol tetrabenzoate, cumylphenyl benzoate, trimethyl pentanediol dibenzoate.
  • solvents include methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate, tert -butyl benzoate, isoamyl benzoate and benzyl benzoate, with benzyl benzoate being most especially preferred.
  • Preferred solvent mixtures are those in which benzyl benzoate is the primary solvent, and mixtures formed of benzyl benzoate and either triacetin, tributyl citrate, triethyl citrate or N-methyl-2-pyrrolidone.
  • Preferred mixtures are those in which benzyl benzoate is present by weight in an amount of 50% or more, more preferably 60% or more and most preferably 80% or more of the total amount of solvent present.
  • Especially preferred mixtures are those of 80/20 mixtures by weight of benzyl benzoate/triacetin and benzyl benzoate/N-methyl-2-pyrrolidone.
  • component solvents may be mixed with one or more additional miscible solvents (“component solvents").
  • component solvents compatible and miscible with the primary solvent may have a higher miscibility with water and the resulting mixtures may still exhibit significant restriction of water uptake into the implant.
  • Such mixtures will be referred to as "component solvent mixtures.”
  • Useful component solvent mixtures may exhibit solubilities in water greater than the primary solvents themselves, typically between 0.1 weight percent and up to and including 50 weight percent, preferably up to and including 30 weight percent, and most preferably up to an including 10 weight percent, without detrimentally affecting the restriction of water uptake exhibited by the implants of the invention.
  • component solvent mixtures having a solubility in water of about 0.1 % to about 7% by weight.
  • Component solvents useful in component solvent mixtures are those solvents that are miscible with the primary solvent or solvent mixture, and include, but are not limited, to triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ket
  • the primary solvent is selected from lower alkyl and aralkyl esters of benzoic acid and the polymer is a lactic-acid based polymer, most preferably PLGA, having a number average molecular weight of between about 8,000 to about 13,000, preferably about 10,000.
  • the most preferred solvents are benzyl benzoate and the lower alkyl esters of benzoic acid.
  • the benzoic acid esters may be used alone or in a mixture with other miscible solvents, e.g., triacetin, as described herein.
  • Implants are prepared as viscous gels in which the beneficial agent is dissolved or dispersed substantially throughout, and such compositions are useful both for systemic and local administration of beneficial agent, whether or not initial burst is an important consideration. Additionally, use of esters of benzoic acid provides increased control of water migration resulting in increased stability of beneficial agent. The low water uptake, i.e., limited water migration into the gel composition after implantation, permits the practitioner of the invention to limit beneficial agent transfer by diffusion and enhance control of the delivery profile of the beneficial agent by controlling the bioerosion characteristics of the polymer.
  • the preferred compositions allow beneficial agent to be loaded into the interior of the polymer at levels that are above that required to saturate the beneficial agent in water, thereby facilitating zero order release of beneficial agent. Additionally, the preferred compositions may provide viscous gels that have a glass transition temperature that is less than 37°C, such that the gel remains non-rigid for a period of time after implantation of 24 hours or more.
  • the solvent or solvent mixture is capable of dissolving the polymer to form a viscous gel that can maintain particles of the beneficial agent dissolved or dispersed and isolated from the environment of use prior to release.
  • the compositions of the present invention provide implants having a low burst index. Water uptake is controlled by the use of a solvent or component solvent mixture that solublizes or plasticizes the polymer but substantially restricts uptake of water into implant.
  • Water uptake was determined for various polymer vehicles, i.e., 50% polymer-50% solvent compositions, in the absence of beneficial agent. As shown in Figure 4A, water uptake by a gel vehicle formed with the more water miscible solvent N-methyl-2-pyrrolidone (NMP) is higher than that for any other solvent-polymer combination, by about a factor of four or more. Water uptake for the combination of 80% benzyl benzoate and 20% NMP by weight in the solvent portion of the vehicle is less than a third that of NMP alone. Implants with benzyl benzoate take up the least water, whether compared to the other solvents alone or as mixtures with benzyl benzoate.
  • NMP water miscible solvent N-methyl-2-pyrrolidone
  • the 80/20 mixture of benzyl benzoate and triacetin takes up less than 10% water on a weight basis, and exhibits less water uptake than triacetin alone.
  • Figure 4B provides a comparison of various solvents alone and demonstrates again the advantages of the benzoic acid esters, particularly that of benzyl benzoate.
  • a relative comparison of the water uptake for the various solvents and the burst indices reproduced in the foregoing Table 1 show a correlation between low water uptake values and low burst indices.
  • Gel compositions of this invention may take up 25 % or less of their bulk weight in water within the first 7 days, 30% in the first 14 days and 40% in the first 21 days, as tested in the water migration assay described herein.
  • agents that modulate the water solubility of the beneficial agent can also be utilized in conjunction with the preferred solvents to control burst of beneficial agent from the implant.
  • Burst indices and percent of beneficial agent released in the first twenty-four hours after implantation may be reduced by one-third to two-thirds or more by the use of solubility modulators associated with the beneficial agent.
  • Such modulators are typically coatings, substances that form complexes or otherwise associate with or stabilize the beneficial agent such as metallic ions, other stabilizing agents, waxes, lipids, oils, nonpolar emulsions, and the like.
  • solubility modulators may permit the use of more highly water soluble solvents or mixtures and achieve burst indices of 8 or less for systemic applications, or with respect to local applications, release of beneficial agent in the first 24 hours after implantation of not greater than 20% of the beneficial agent administered. Preferably that release will be not greater than 15% and more preferably not greater than 10%.
  • compositions of this invention can often provide the opportunity to prepare compositions without solubility modulators when in other compositions such modulators would be necessary.
  • suitable burst indices are obtained for a composition of PLGA, benzyl benzoate and human growth hormone without the presence of Zn ion.
  • Similar results may be obtained with other beneficial agents, such as the interferons, including interferon alpha-2a, interferon alpha-2b and consensus interferon.
  • compositions of the present invention may be desirable to add osmotic agents or other agents and hydroattractants that facilitate water uptake to desired levels.
  • agents may be, for example, sugars and the like, and are well known in the art.
  • a composition of the present invention takes the form of a substantially, homogeneous, sponge-like gel, with the pores in the interior of the implant being much the same as the pores on the surface of the implant.
  • Compositions of the present invention retain their gel-like consistency over a longer period than do prior art devices and permit beneficial agent to be delivered over a prolonged period.
  • the implants of the present invention generally have a glass transition temperature, T g , of less than body temperature of the subject, e.g. 3TC for humans. Because of the immiscibility of the solvents that are useful in this invention with water, water uptake by the implant is restricted and the pores that do form tend to resemble a closed cell structure without significant numbers of larger pores or pores extending from the surface into the interior of the implant being open at the surface of the implant. Furthermore, the surface pores offer only a limited opportunity for water from body fluids to enter the implant immediately after implantation, thus controlling the burst effect.
  • the viscosity optionally may be modified by the use of viscosity-reducing, miscible solvents or the use of emulsifiers, or by heating to obtain a gel composition having a viscosity or shear resistance low enough to permit passage of the gel composition through a needle.
  • the limit on the amount of beneficial agent released in the first 24 hours that is either desired or required will depend on circumstances such as the overall duration of the delivery period, the therapeutic window for the beneficial agent, potential adverse consequences due to overdosing, cost of beneficial agent, and the type of effect desired, e.g., systemic or local.
  • 20% or less of the beneficial agent will be released in the first 24 hours after implantation, where the percentage is based on the total amount of beneficial agent to be delivered over the duration of the delivery period.
  • higher percentages of release in the first 24 hours can be tolerated if the duration of the delivery period is relatively short, e.g., less than 7-14 days, or if the beneficial agent has a wide therapeutic window with little likelihood of side effects, or if the beneficial agent acts locally.
  • the compositions of the present invention intended for systemic delivery may provide a gel composition having a burst index of 8 or less, preferably 6 or less, more preferably 4 or less and most preferably 2 or less.
  • Compositions of PLGA with solvents having a miscibility in water of less than 7% by weight, optionally combined with the other solvents, providing implants intended for systemic delivery of beneficial agent having a burst index of 10 or less, preferably 7 or less, more preferably 5 or less and most preferably 3 or less, are particularly advantageous.
  • the use of solvent mixtures as discussed herein can be particularly advantageous as a means of providing sufficient plasticizing of the polymer to obtain viscous gel formation and at the same time meet the desired burst indices and percentage release objectives of the compositions of the invention.
  • compositions intended for local delivery of beneficial agent are formed in the same manner as those intended for systemic use. However, because local delivery of beneficial agent to a subject will not result in detectable plasma levels of beneficial agent, such systems have to be characterized by a percentage of beneficial agent released in a predetermined initial period, rather than a burst index as defined herein. Most typically, that period will be the first 24 hours after implantation and the percentage will be equal to the amount by weight of the beneficial agent released in the period (e.g. 24 hours) divided by the amount by weight of the beneficial agent intended to be delivered in the duration of the delivery period: multiplied by the number 100.
  • Compositions of the present invention will have initial bursts of 20% or less, preferably 15% or less, most preferably 10% or less, for most applications. Especially preferred are implant systems having initial bursts of 5% or less.
  • implants of the invention containing chemotherapeutic agents are suitable for direct injection into tumors.
  • many chemotherapeutic agents may exhibit toxic side effects when administered systemically. Consequently, local administration into the tumor may be the treatment method of choice. It is necessary, however, to avoid administration of a large burst of the chemotherapeutic agent if it is possible that such agent would enter the vascular or lymphatic systems where it may exhibit side affects. Accordingly, in such instances the implantable systems of the present invention having limited burst as described herein are advantageous.
  • the solvent or solvent mixture is typically present in an amount of from about 95 to about 20% by weight and is preferably present in an amount of from about 70 to about 30% by weight and often 60-40% by weight of the viscous gel, i.e., the combined amounts of the polymer and the solvent.
  • the viscous gel formed by mixing the polymer and the solvent typically exhibits a viscosity of from about 1,000 to about 200,000 poise, preferably from about 5,000 to about 50,000 poise measured at a 1.0 sec -1 shear rate and 25°C using a Haake Rheometer at about 1-2 days after mixing is completed.
  • compositions can be achieved with conventional low shear equipment such as a Ross double planetary mixer for from about 10 minutes to about 1 hour, although shorter and longer periods may be chosen by one skilled in the art depending on the particular physical characteristics of the composition being prepared. Since it is often desirable to administer the implant as an injectable composition, a countervailing consideration when forming implants that are viscous gels is that the polymer/solvent/beneficial agent composition have sufficiently low viscosity in order to permit it to be forced through a small diameter, e.g., 18-20 gauge needle. If necessary, adjustment of viscosity of the gel for injection can be accomplished with emulsifying agents as described herein. Yet, such compositions should have adequate dimensional stability so as to remain localized and be able to be removed if necessary. The particular gel or gel-like compositions of the present invention satisfy such requirements.
  • the level of polymer dissolution will need to be balanced with the resulting gel viscosity, to permit a reasonable force to dispense the viscous gel from a needle, and the potential burst effect.
  • Highly viscous gels enable the beneficial agent to be delivered without exhibiting a significant burst effect, but may make it difficult to dispense the gel through a needle.
  • an emulsifying agent may optionally be added to the composition.
  • the viscosity may generally be lowered as the temperature of the composition increases, it may be advantageous in certain applications to reduce the viscosity of the gel by heating to provide a more readily injectable composition.
  • a gel prepared from 40% by weight of a 50:50 lactic acid:glycolic polymer and 60% by weight of triacetin required about 40 psig to dispense the gel through a standard 20 gauge needle at 2 cc/min while a gel prepared from the same amount of polymer with 60% by weight of N-methyl-2-pyrrolidone required only about 8 psig.
  • Figure 1 further shows that when the emulsifying agent (in this case 33% by weight of a 10% ethanol solution) is added to the viscous gel according to the invention, the dispense force needed is only about 2 psig.
  • the shear thinning characteristics of the depot gel compositions of the present invention allow them to be readily injected into an animal including humans using standard gauge needles without requiring undue dispensing pressure.
  • the emulsifying agent When the emulsifying agent is mixed with the viscous gel formed from the polymer and the solvent using conventional static or mechanical mixing devices, such as an orifice mixer, the emulsifying agent forms a separate phase composed of dispersed droplets of microscopic size that typically have an average diameter of less than about 100 microns.
  • the continuous phase is formed of the polymer and the solvent.
  • the particles of the beneficial agent may be dissolved or dispersed in either the continuous phase or the droplet phase.
  • the droplets of emulsifying agent elongate in the direction of shear and substantially decrease the viscosity of the viscous gel formed from the polymer and the solvent.
  • a viscous gel having a viscosity of from about 5,000 to about 50,000 poise measured at 1.0 sec -1 at 25°C. one can obtain a reduction in viscosity to less than 100 poise when emulsified with a 10% ethanol/water solution at 25°C as determined by Haake Rheometer.
  • the emulsifying agent typically is present in an amount ranging from about 5 to about 80%, preferably from about 20 to about 60% and often 30 to 50% by weight based on the amount of the injectable depot gel composition, that is the combined amounts of polymer, solvent, emulsifying agent and beneficial agent.
  • Emulsifying agents include, for example, solvents that are not fully miscible with the polymer solvent or solvent mixture.
  • Illustrative emulsifying agents are water, alcohols, polyols, esters, carboxylic acids, ketones, aldehydes and mixtures thereof.
  • Preferred emulsifying agents are alcohols, propylene glycol, ethylene glycol, glycerol, water, and solutions and mixtures thereof.
  • emulsifying agent affects the size of the dispersed droplets.
  • ethanol will provide droplets that have average diameters that can be on the order of ten times larger than the droplets obtained with an isotonic saline solution containing 0.9% by weight of sodium chloride at 21 °C.
  • Figure 3 shows the viscosities at different shear rates using water alone and an aqueous mixture containing 10% by volume of ethanol at a weight ratio of 2:1 (gel:emulsifying agent) using a viscous gel formed from 50% by weight of a 50:50 lactic acid:glycolic acid copolymer and 50% by weight of triacetin compared to the viscosities of the viscous gel without emulsifying agent.
  • the emulsifying agent does not constitute a mere diluent that reduces viscosity by simply decreasing the concentration of the components of the composition.
  • the use of conventional diluents can reduce viscosity, but can also cause the burst effect mentioned previously when the diluted composition is injected.
  • the injectable depot composition of the present invention can be formulated to avoid the burst effect by selecting the solvent and emulsifying agent so that once injected into place, the emulsifying agent has little impact on the release properties of the original system.
  • the means of administration of the implants is not limited to injection, although that mode of delivery may often be preferred.
  • the implant may be formed to fit into a body cavity existing after completion of surgery or it may be applied as a flowable gel by brushing or palleting the gel onto residual tissue or bone. Such applications may permit loading of beneficial agent in the gel above concentrations typically present with injectable compositions.
  • the beneficial agent can be any physiologically or pharmacologically active substance or substances optionally in combination with pharmaceutically acceptable carriers and additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. that do not substantially adversely affect the advantageous results that can be attained by the present invention.
  • the beneficial agent may be any of the agents which are known to be delivered to the body of a human or an animal and that are preferentially soluble in water rather than in the polymer-dissolving solvent. These agents include drug agents, medicaments, vitamins, nutrients, or the like. Included among the types of agents which meet this description are lower molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors and fertility promoters.
  • Drug agents which may be delivered by the present invention include drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system.
  • Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, antiinflammatory corticosteroids, ocular drugs and synthetic analogs of these species.
  • proteins and peptides which include, but are not limited to, bone morphogenic proteins, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin. GRF.
  • somatostatin lypressin, pancreozymin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferons such as interferon alpha-2a, interferon alpha-2b, and consensus interferon, interleukins, growth hormones such as human growth hormone and its derivatives such as methione-human growth hormone and des-phenylalanine human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors such as insulin-like growth factor, coagulation factors, human pancreas hormone releasing factor, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives.
  • interferons such as interferon alpha-2a, interferon alpha-2b, and consensus interferon, interleukins
  • growth hormones such as human growth hormone and its derivatives such as methione-human growth hormone and des-phenylalanine human growth hormone
  • the present invention also finds application with chemotherapeutic agents for the local application of such agents to avoid or minimize systemic side effects.
  • Gels of the present invention containing chemotherapeutic agents may be injected directly into the tumor tissue for sustained delivery of the chemotherapeutic agent over time.
  • the gel may be implanted directly into the resulting cavity or may be applied to the remaining tissue as a coating.
  • chemotherapeutic agents that may be delivered in accordance with the practice of the present invention include, for example, carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecin, etopside, cytokines, ribozymes, interferons, oligonucleotides and oligonucleotide sequences that inhibit translation or transcription of tumor genes, functional derivatives of the foregoing, and generally known chemotherapeutic agents such as those described in U.S. Patent 5,651,986.
  • the present application has particular utility in the sustained delivery of water soluble chemotherapeutic agents, such as for example cisplatin and carboplatin and the water soluble derivatives of paclitaxel.
  • Those characteristics of the invention that minimize the burst effect are particularly advantageous in the administration of water soluble beneficial agents of all kinds, but particularly those compounds that are clinically useful and effective but may have adverse side effects.
  • beneficial agents described in aforementioned U.S. Patent No. 5,242,910 can also be used.
  • One particular advantage of the present invention is that materials, such as proteins, as exemplified by the enzyme lysozyme, and cDNA, and DNA incorporated into vectors both viral and nonviral, which are difficult to microencapsulate or process into microspheres can be incorporated into the compositions of the present invention without the level of degradation caused by exposure to high temperatures and denaturing solvents often present in other processing techniques.
  • the beneficial agent is preferably incorporated into the viscous gel formed from the polymer and the solvent in the form of particles typically having an average particle size of from about 0.1 to about 100 ⁇ m preferably from about 1 to about 25 ⁇ m and often from 2 to 10 ⁇ m
  • particles having an average particle size of about 5 ⁇ m have been produced by spray drying or freeze drying an aqueous mixture containing 50% sucrose and 50% chicken lysozyme (on a dry weight basis) and mixtures of 10-20% hGH and 15-30 mM zinc acetate.
  • Conventional lyophilization processes can also be utilized to form particles of beneficial agents of varying sizes using appropriate freezing and drying cycles.
  • any conventional low shear device can be used such as a Ross double planetary mixer at ambient conditions. In this manner, efficient distribution of the beneficial agent can be achieved substantially without degrading the beneficial agent.
  • the beneficial agent is typically dissolved or dispersed in the composition in an amount of from about 1 to about 50% by weight, preferably in an amount of from about 5 to about 30% and often 10 to 20% by weight of the combined amounts of the polymer, solvent and beneficial agent.
  • beneficial agent present in the composition one can obtain different release profiles and burst indices. More specifically, for a given polymer and solvent, by adjusting the amounts of these components and the amount of the beneficial agent, one can obtain a release profile that depends more on the degradation of the polymer than the diffusion of the beneficial agent from the composition or vice versa. In this respect, at lower beneficial agent loading rates, one generally obtains a release profile reflecting degradation of the polymer wherein the release rate increases with time.
  • beneficial agent will be adjusted to provide for therapeutically-effective delivery of the beneficial agent over the intended sustained delivery period.
  • the beneficial agent will be present in the polymer gel at concentrations that are above the saturation concentration of beneficial agent in water to provide a drug reservoir from which the beneficial agent is dispensed.
  • release rates on the order of from about 0.1 to about 100 micrograms/day, preferably from about 1 to about 10 micrograms per day, for periods of from about 7 to about 90 days can be obtained. Greater amounts may be delivered if delivery is to occur over shorter periods. Generally, higher release rate is possible if a greater burst can be tolerated.
  • the gel composition is surgically implanted, or used as a "leave behind" depot when surgery to treat the disease state or another condition is concurrently conducted, it is possible to provide higher doses that would normally be administered if the implant was injected.
  • the dose of beneficial agent may be controlled by adjusting the volume of the gel implanted or the injectable gel injected. As can be seen from Figure 2 with respect to lysozyme, with more highly viscous systems, one can avoid a burst effect and deliver on the order of 1% by weight of the beneficial agent in the composition during the first day.
  • FIGs 5A and 5B illustrate representative release profiles of human growth hormone ("hGH") obtained in rats from preferred compositions of this invention.
  • hGH human growth hormone
  • the benefits of benzyl benzoate are apparent in that comparison.
  • the hGH-benzyl benzoate implant shows a lower burst and a nearly zero order sustained release of hGH over the release period for both the case wherein the hGH is not stabilized ( Figure 5A) and the case in which hGH is stabilized with zinc ions (Figure 5B).
  • compositions may be present in the gel composition, to the extent they are desired or provide useful properties to the composition, such as polyethylene glycol, hydroscopic agents, stabilizing agents, pore forming agents, and others.
  • a solubility modulator that may, for example, be a stabilizing agent, in the composition.
  • Various modulating agents are described in U.S. Patent Nos. 5.654,010 and 5,656,297.
  • hGH for example, it is preferable to include an amount of a salt of a divalent metal, preferably zinc.
  • modulators and stabilizing agents which may form complexes with the beneficial agent or associate to provide the stabilizing or modulated release effect, include metal cations, preferably divalent, present in the composition as magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, zinc chloride, magnesium chloride, magnesium oxide, magnesium hydroxide, other antacids, and the like.
  • the amounts of such agents used will depend on the nature of the complex formed, if any, or the nature of the association between the beneficial agent and the agent. Molar ratios of solubility modulator or stabilizing agent to beneficial agent of about 100:1 to 1:1, preferably 10:1 to 1:1, typically can be utilized.
  • Pore forming agents include, biocompatible materials that when contacted with body fluids dissolve, disperse or degrade to create pores or channels in the polymer matrix.
  • organic and non-organic materials that are water soluble such as sugars (e.g., sucrose, dextrose), water soluble salts (e.g., sodium chloride, sodium phosphate, potassium chloride, and sodium carbonate), water soluble solvents such as N-methyl-2-pyrrolidone and polyethylene glycol and water soluble polymers (e.g., carboxmethylcellulose, hydroxypropylcellulose, and the like) can conveniently be used as pore formers.
  • Such materials may be present in amounts varying from about 0.1% to about 100% of the weight of the polymer, but will typically be less than 50% and more typically less than 10-20% of the weight of polymer.
  • compositions of this invention without beneficial agent are useful for wound healing, bone repair and other structural support purposes.
  • Lysozyme particles were made by spray drying 50% sucrose and 50% chicken lysozyme (on a dry weight basis).
  • a viscous gel material was prepared by heating 60% by weight of triacetin with 40% by weight of a 50:50 lactic acid:glycolic acid copolymer to 37°C overnight. The viscous gel was allowed to cool to room temperature. The lysozyme particles were added to the viscous gel in a ratio of 20:80 lysozyme particles:gel (by weight). The combination was mixed for 5 minutes. Immediately prior to use, a 10% ethanol, 90% isotonic saline solution was added as the emulsifying agent. The emulsifying agent comprised 1/3 of the total injectable depot gel composition. The prepared compositions were suitable for injection.
  • Figure 2 shows the in vitro release rates obtained from the compositions described with regard to Figure 1.
  • the gel prepared from 40% by weight of a 50:50 lactic acid:glycolic polymer and 60% by weight triacetin is thick and thus difficult to inject but shows little burst (less than 2% of the beneficial agent is delivered in the first eight days).
  • the gel prepared from 40% by weight of a 50:50 lactic acid:glycolic polymer and 60% by weight n-methyl-2-pyrrolidone is thin and injectable but shows a large burst (greater than 70% of the beneficial agent is delivered in the first eight days).
  • the gel prepared from 27% by weight of a 50:50 lactic acid:glycolic polymer, 40% by weight triacetin and 33% by weight of a 10% ethanol, 90% isotonic saline solution is thin and injectable and shows little burst (less than 10% of the beneficial agent is delivered in the first eight days).
  • lysozyme is the beneficial agent and comprises 20% by weight of the combined beneficial agent, polymer and solvent formulation.
  • Human growth hormone (hGH) particles (optionally containing zinc acetate) were prepared as follows:
  • hGH solution (5 mg/ml) solution in water (BresaGen Corporation, Sydney, Australia) was concentrated to 10 mg/mL using a Concentration/Dialysis Selector diafiltering apparatus. The diafiltered hGH solution was then washed with 5 times volume of tris or phosphate buffer solution (pH 7.6). Particles of hGH were then formed by spray drying or lyophilization using conventional techniques.
  • Phosphate buffer solutions (5 or 50 mM) containing hGH (5 mg/mL) and various levels of zinc acetate (0 to 30 mM) were spray-dried using a Yamato Mini Spraydryer set at the following parameters: Spray Dryer Parameter Setting Atomizing Air 2 psi Inlet Temperature 120°C Aspirator Dial 7.5 Solution Pump 2-4 Main Air Valve 40-45 psi hGH particles having a size range between 2 - 100 microns were obtained.
  • Lyophilized particles were prepared from tris buffer solutions (5 or 50 mM: pH 7.6) containing hGH (5 mg/mL) and various levels of zinc acetate (0 to 30 mM) using a Durastop ⁇ P Lyophilizer in accordance with the following freezing and drying cycles: Freezing Cycle Ramp down at 2.5 C/min to -30 C and hold for 30 minutes Ramp down at 2.5 C/min from -30 C to -50C and hold for 60 minutes Drying Cycle Ramp up at 0.5 C/min to 10 C and hold for 960 min Ramp up at 0.5 C/min to 20 C and hold for 480 min Ramp up at 0.5 C/min to 25 C and hold for 300 min Ramp up at 0.5 C/min to 30 C and hold for 300 min Ramp down at 0.5 C/min to 5 C and hold for 5000 min hGH particles having a size range between 2 - 100 microns were obtained.
  • Zinc acetate solutions were prepared with tris buffer and phosphate buffer. Desired molar volumes of trizma hydrochloride and trizma base were prepared separately (5 or 50 mM). The pH of trizma base solution was measured, and the corresponding trizma hydrochloride solution was added to adjust the pH of the trizma base solution, resulting with a final pH of 7.6. The desired molar volume of zinc acetate was added to the buffer solution. Desired molar volumes of sodium phosphate monobasic and sodium phosphate diabasic were prepared separately (5 or 50 mM). Sodium azide (0.2% w/w) was added to each phosphate solution.
  • the pH of the dibasic solution was measured, and the corresponding monobasic solution was added to adjust the pH of the dibasic solution, resulting with a final pH of 7.6.
  • the desired molar volume of zinc acetate was added to the buffer solution.
  • Tris or phosphate buffer containing zinc acetate was added to the diafiltered hGH solution to achieve the final desired zinc acetate molar volume (between 5 and 30 mM).
  • the final hGH concentration was 5 mg/mL.
  • a glass vessel was tared on a Mettler PJ3000 top loader balance.
  • Poly (D,L-lactide-co-glycolide) 50:50 RESOMER® RG502 (PLGA-502) was weighed into the glass vessel.
  • the glass vessel containing PLGA-502 was tared and the corresponding solvent was added. Amounts expressed as percentages for various polymer/solvent combinations are set forth in Table 2 below.
  • the polymer/solvent mixture was manually stirred with a stainless steel square-tip spatula, resulting in a sticky amber paste-like substance containing white polymer particles.
  • the vessel containing the polymer/solvent mixture was sealed and placed in a temperature controlled incubator equilibrated to 39°C.
  • the polymer/solvent mixture was removed from the incubator when it appeared to be a clear amber homogeneous gel. Incubation time intervals ranged from 1 to 4 days, depending on solvent and polymer type and solvent and polymer ratios. Additional depot gel vehicles are prepared with the following polymers: Poly (D,L-lactide-co-glycolide) 50:50 RESOMER® L104, PLGA-L104, code no. 33007, Poly (D,L-lactide-co-glycolide) 50:50 RESOMER® RG206, PLGA-206, code no.
  • Table 2 Gel Vehicles Solvent/Polymer Solvent Polymer Amount Solvent Amount Polymer Gel Weight Ratio 50/50 BB PLGA-502 5 g 5 g 10 g 1.0 50/50 TA / BB Mixture PLGA-502 5 g 5 g 10 g 1.0 60/40 TA / BB Mixture PLGA-502 6 g 4 g 10 g 1.5 70/30 TA / BB Mixture PLGA-502 7 g 3 g 10 g 2.3 80/20 TA / BB Mixture PLGA-502 8 g 2 g 10 g 4 0 50150 EB PLGA-502 5 g 5 g 10 g 1 0 50/50 TA / EB Mixture PLGA-502 5 g 5 g 10 1.0 50/50 BB PLGA-502 25 g 25 g 50 g 1.0 55/45 BB PLGA-502 27.5 g 22.5 g 50 g 1 2 50/50 BB
  • Spray-dried or lyophilized hGH particles (10 - 20% w/w), with and without zinc acetate, prepared as above were added to a specified clear amber depot gel vehicle and blended manually until the dry powder was wetted completely. Then, the milky light yellow particle/gel mixture was thoroughly blended by conventional mixing using a Caframo mechanical stirrer with an attached square-tip metal spatula. Resulting formulations are illustrated in Tables 3 and 4 below. "L” identifies lyophilized hGH particles and "SD" identifies spray dried hGH particles. Final homogenous gel formulations were transferred to 3, 10 or 30 cc disposable syringes for storage or dispensing.
  • Table 3 In Vivo hGH Formulation Polymer Solvent Drug Particle Tnzma Buffer (mM) Level PLGA Level Type Level Process Zinc Level (mM) A 45% 502 45% TA 10% L 0 50 B 45% 502 45% TA 10% L 7.5 50 C 45% 502 45% TA 10% L 15 50 D 45% 502 45% BB 10% L 0 50 E 45% 502 45% BB 10% L 7.5 50 F 45% 502 45% BB 10% L 15 50 G 45% 502 45% NMP 10% L 0 50 H 45% 502 45% NMP 10% L 15 50 I 45% 502 45% TA 10% SD 0 50 J 45% 502 45% TA 10% SD 75 50 K 45% 502 45% BB 10% SD 0 50 L 45% 502 45% BB 10% SD 7.5 50 Table 4.
  • Lysozyme from chicken egg white (Sigma Chemical Co., St Louis, MO) in vitro release studies were used to test different vehicle formulations with the highly water soluble solvent NMP and the less soluble solvents triacetin and benzyl benzoate useful in the present invention.
  • a depot gel formutation was dispensed from a 3 cc disposable syringe and weighed onto a DelrinTM cup platform or a 250 ⁇ mesh 1 square inch polypropylene screen. Then, the cup or screen containing a depot gel formulation was immersed into a plastic cup or screen containing a depot gel formulation was immersed into a plastic vial containing 10 mL of receptor buffer. A snap-on lid was placed onto the plastic vial to prevent evaporation.
  • the vial containing the depot gel formulation was immersed into a Haake shaking water bath equilibrated to 37°C. At each time point, forceps were used to transfer DelrinTM cup platforms or polypropylene screen platforms containing depot gel formulations to new plastic vials containing 10 mL of receptor buffer. Disposable transfer pipettes were used to transfer receptor samples to HPLC vials.
  • the receptor buffer was phosphate buffered saline, PBS, adjusted to pH 7 containing sodium azide (0.2%).
  • Receptor buffers contained tween-80 (0.1 %) for most cases. Collection intervals were typically 2, 4, 8 hours, 1, 2, 3, 4, 7, 10 days, and 2, 3, 4, 5, 6, 7, 8 weeks.
  • Example 3 The same procedure was used as described in Example 3 for in vitro drug release using the DelrinTM cup platform, except the entire cup platform containing the depot gel vehicle was removed, blotted dry, and placed in a dry plastic vial at specified time intervals. The receptor solution was sterile water and replaced at each time interval for the remaining samples. Initial and final depot gel vehicle weights were recorded to observe weight change. Water content was obtained from depot gel vehicles using a Karl Fischer Apparatus, Mitsubishi Moisture Meter CA-06 equipped with Vaporizer VA-06. Results are illustrated in Figures 4A-4B for selected gels. Those results demonstrate that gel compositions of this invention take up substantially less water than gel compositions formed with NMP alone.
  • Implant systems of this invention are prepared in accordance with Example 2 with equivalent quantities of interferon alpha-2a and -2b, consensus interferon, methionine human growth hormone, des-phenylalanine human growth hormone, carboplatin and insulin-like growth factor.
  • the amount of the viscous gel containing drug administered to rats in accordance with Example 5 is adjusted to take into account the relative biological activity of the separate agents.
  • the implant systems are implanted in rats to provide systemic levels of active agent.
  • Implant systems containing carboplatin are prepared according to Example 6 and injected directly into solid tumors of tumor bearing rats.
  • the implant systems are suitable for local delivery of carboplatin to tumors.
  • 100 Mg implantable depots containing 0.5, 1.5 and 3 mg of interferon alpha-2b, stabilized with 0.5, 1 and 2 mg of sucrose, respectively, and the remainder being 50 mg benzyl benzoate and 45-49 mg of PLGA 502 as applicable (number average molecular weight of about 10,000) are prepared in accordance with Example 2 (without the addition of zinc).
  • the implants exhibit limited burst and are suitable for implantation.
  • the implant systems are implanted in rats to provide systemic levels of interferon alpha-2b.
  • implantable or injectable viscous gels containing beneficial agent for systemic and local administration are obtained that exhibit low or minimal burst effect when implanted.
  • implantable or injectable viscous gels containing beneficial agent for systemic and local administration are obtained that exhibit low or minimal burst effect when implanted.
  • the beneficial agent once the beneficial agent has been fully administered, there is no need to remove the composition since it is fully biodegradable.
  • the present invention avoids the use of microparticle or microencapsulation techniques which can degrade certain beneficial agents, like peptide and nucleic acid-based drugs and which microparticles and microcapsules may be difficult to remove from the environment of use. Since the viscous gel is formed without the need for water, temperature extremes, or other solvents, suspended particles of beneficial agent remain dry and in their original configuration, which contributes to the stability of thereof. Further, since a mass is formed, the injectable depot gel composition may be retrieved from the environment of use if desired.

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Claims (26)

  1. Composition biodégradable, implantable, pour l'administration entretenue d'un agent utile à un sujet, dans laquelle la composition comprend un polylactide polymère; une quantité plastifiante efficace d'au moins un solvant pour former un gel visqueux avec le polymère; et un agent utile dissous ou dispersé dans le gel, dans laquelle le solvant est choisi dans le groupe constitué par le benzoate de méthyle, le benzoate d'éthyle, le benzoate de n-propyle, le benzoate d'isopropyle, le benzoate de butyle, le benzoate d'isobutyle, le benzoate de sec.-butyle, le benzoate de tert.-butyle, le benzoate d'isoamyle, le dibenzoate de 1,4-cyclohexane diméthanol, le dibenzoate de diéthylène glycol, le dibenzoate de dipropylène glycol, le dibenzoate de polypropylène glycol, le dibenzoate de propylène glycol, un mélange de benzoate de diéthylène glycol et de benzoate de dipropylène glycol, le dibenzoate de polyéthylène glycol (200), le benzoate d'isodécyle, le dibenzoate de néopentyl glycol, le tribenzoate de glycéryle, le tétrabenzoate de pentaérythritol, le benzoate de cumylphényle, le dibenzoate de triméthyl pentanediol, et leurs mélanges.
  2. Composition selon la revendication 1, dans laquelle la miscibilité dans l'eau du mélange solvant est de 10 % ou moins en poids.
  3. Composition selon l'une des revendications 1 ou 2, dans laquelle le polymère est à base d'acide lactique.
  4. Composition selon l'une quelconque des revendications précédentes, dans laquelle le au moins un solvant est le benzoate d'éthyle.
  5. Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition a au moins l'une des propriétés suivantes : elle imbibe 40% ou moins de son poids en vrac dans l'eau dans les 21 premiers jours après l'implantation ; elle imbibe moins de 30% de son poids en vrac dans l'eau dans les 14 premiers jours après l'implantation ; ou elle imbibe moins de 25 % de son poids en vrac dans l'eau dans les 7 premiers jours après l'implantation.
  6. Composition selon la revendication 5, dans laquelle l'agent utile est choisi parmi l'ADNc, l'ADN, les peptides, les protéines, et leurs fragments et dérivés.
  7. Composition selon l'une quelconque des revendications précédentes, dans laquelle la quantité totale de solvant représente 40% ou plus en poids du véhicule de gel, ladite composition ayant un indice d'éclatement de 8 ou moins.
  8. Composition selon la revendication 7, dans laquelle le gel est adapté pour rester non rigide après l'implantation.
  9. Composition selon l'une des revendications 7 ou 8, dans laquelle le gel est adapté pour conserver une température de transition vitreux au-dessous de 37°C pendant au moins 24 heures après l'implantation.
  10. Composition selon l'une quelconque des revendications précédentes, dans laquelle le polymère est un copolymère poly(lactide-co-glycolide); le solvant limite la quantité d'imbibition d'eau de la composition ; l'agent utile est choisi parmi l'ADNc, l'ADN, les peptides, les protéines, et leurs fragments et dérivés ; et la composition a un indice d'éclatement égal ou inférieur à 8.
  11. Composition selon la revendication 10, dans laquelle le polymère a un rapport de monomères d'acide lactique à acide glycolique se situant dans la plage de 100 : 0 à 15 : 85.
  12. Composition selon l'une des revendications 10 ou 11, dans laquelle le copolymère a une masse moléculaire moyenne en nombre de 1000 à 120 000.
  13. Composition selon l'une quelconque des revendications précédentes, dans laquelle le solvant comprend un solvant constitutif miscible avec le solvant.
  14. Composition selon la revendication 13, dans laquelle le solvant constitutif est choisi parmi la triacétine, la diacétine, la tributyrine, le citrate de triéthyle, le citrate de tributyle, le citrate d'acétyle et de triéthyle, le citrate d'acétyle et de tributyle, les triéthylglycérides, le phosphate de triéthyle, le phtalate de diéthyle, le tartrate de diéthyle, l'huile minérale, le polybutène, le fluide de silicone, la glycérine, l'éthylène glycol, le polyéthylène glycol, l'octanol, le lactate d'éthyle, le propylène glycol, le carbonate de propylène, le carbonate d'éthylène, la butyrolactone, l'oxyde d'éthylène, l'oxyde de propylène, la N-méthyl-2-pyrrolidone, la 2-pyrrolidone, le glycérol formal, l'acétate de méthyle, l'acétate d'éthyle, la méthyl éthyl cétone, le diméthylformamide, le diméthyl sulfoxyde, le tétrahydrofuranne, le caprolactame, le décylméthyl sulfoxyde, l'acide oléique et la 1-dodécylazacyclo-heptan-2-one, et leurs mélanges.
  15. Composition selon l'une des revendications 13 ou 14, dans laquelle le solvant constitutif est l'un ou l'autre parmi la triacétine, la N-méthyl-2-méthylpyrrolidone ou leurs mélanges.
  16. Composition selon l'une quelconque des revendications précédentes comprenant en outre au moins l'un des suivants :
    - un agent émulsifiant ;
    - un agent porogène ;
    - un modulateur de solubilité pour l'agent utile; et
    - un agent osmotique.
  17. Composition selon la revendication 16, qui comprend un modulateur de solubilité choisi parmi les sels de métaux divalents.
  18. Composition selon l'une des revendications 16 ou 17, qui comprend un agent porogène soluble dans l'eau.
  19. Composition selon la revendication 18, dans laquelle l'agent porogène est choisi parmi les sucres, les sels, les solvants et les polymères solubles dans l'eau.
  20. Composition selon l'une quelconque des revendications 16 à 19, qui comprend un agent émulsifiant capable de former une phase de gouttelettes dispersées dans ledit gel visqueux.
  21. Composition selon la revendication 20, dans laquelle l'agent émulsifiant est choisi parmi les alcools, le propylène glycol, l'éthylène glycol, le glycérol, l'éthanol, l'eau, l'alcool isopropylique, l'eau et leurs solutions et mélanges.
  22. Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition est implantable, injectable ou un gel pour l'utilisation comme implant ou injection.
  23. Procédé de préparation d'une composition de gel retard injectable, comprenant les opérations consistant à :
    (a) mélanger un polylactide polymère et un solvant choisi dans le groupe constitué par le benzoate de méthyle, le benzoate d'éthyle, le benzoate de n-propyle, le benzoate d'isopropyle, le benzoate de butyle, le benzoate d'isobutyle, le benzoate de sec.-butyle, le benzoate de tert.-butyle, le benzoate d'isoamyle, le dibenzoate de 1,4-cyclohexane diméthanol, le dibenzoate de diéthylène glycol, le dibenzoate de dipropylène glycol, le dibenzoate de polypropylène glycol, le dibenzoate de propylène glycol, un mélange de benzoate de diéthylène glycol et de benzoate de dipropylène glycol, le dibenzoate de polyéthylène glycol (200), le benzoate d'isodécyle, le dibenzoate de néopentyl glycol, le tribenzoate de glycéryle, le tétrabenzoate de pentaérythritol, le benzoate de cumylphényle, le dibenzoate de triméthyl pentanediol, et leurs mélanges, afin de former un gel visqueux;
    (b) disperser ou dissoudre un agent utile, facultativement associé avec un modulateur de solubilité, dans un agent émulsifiant pour former un agent utile contenant un agent émulsifiant; et
    (c) mélanger l'agent utile contenant l'agent émulsifiant avec le gel visqueux, ledit agent utile contenant un agent émulsifiant formant une phase de gouttelettes dispersées dans le gel visqueux, et facultativement
    (d) mélanger un ou plusieurs d'un agent porogène et un agent osmotique avec ledit gel visqueux, pour fournir une composition de gel injectable.
  24. Kit pour l'administration d'un agent utile à un sujet comprenant une composition telle que définie à l'une quelconque des revendications 1 à 22 et un modulateur de solubilité de l'agent utile associé avec l'agent utile, dans lequel au moins l'agent utile associé avec le modulateur de solubilité est maintenu séparé du solvant jusqu'au moment de l'administration de l'agent utile à un sujet.
  25. Utilisation d'une composition telle que définie à l'une quelconque des revendications 1 à 22 pour la fabrication d'un médicament implantable.
  26. Utilisations selon la revendication 25, dans laquelle le médicament implantable est adapté pour libérer en l'espace de 24 heures après l'implantation pas plus de 20 % en poids de la quantité de l'agent utile devant être administré sur la durée de la période d'administration prévue pour l'administration locale de l'agent utile.
EP97952575A 1996-12-20 1997-12-18 Procedes et composition a base de gel Expired - Lifetime EP0959873B1 (fr)

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CA2591581A1 (fr) 1998-07-02
JP2002512597A (ja) 2002-04-23
PT949905E (pt) 2001-12-28
US6673767B1 (en) 2004-01-06
CN1240346A (zh) 2000-01-05
GR3036599T3 (en) 2001-12-31
US20060013879A9 (en) 2006-01-19
CA2275525A1 (fr) 1998-07-02
JP4642946B2 (ja) 2011-03-02
US20020034532A1 (en) 2002-03-21
WO1998027963A2 (fr) 1998-07-02
DE69705746D1 (de) 2001-08-23
ATE318580T1 (de) 2006-03-15
EP0949905B1 (fr) 2001-07-18
CA2275587C (fr) 2006-10-24
AU5609798A (en) 1998-07-17
HK1020009A1 (en) 2000-03-10
DE69735384D1 (de) 2006-04-27
EP0949905A2 (fr) 1999-10-20
US6331311B1 (en) 2001-12-18
KR100616793B1 (ko) 2006-08-28
DE69705746T2 (de) 2001-10-31
CA2275525C (fr) 2011-02-08
WO1998027963A3 (fr) 1998-10-15
HK1023950A1 (en) 2000-09-29
JP2001509146A (ja) 2001-07-10
DK0949905T3 (da) 2001-10-22
ATE203157T1 (de) 2001-08-15
IL130532A0 (en) 2000-06-01
JP2010095544A (ja) 2010-04-30
DK0959873T3 (da) 2006-07-03
US20030044467A1 (en) 2003-03-06
US6468961B1 (en) 2002-10-22
CA2275587A1 (fr) 1998-07-02
CN1146402C (zh) 2004-04-21
KR20000069564A (ko) 2000-11-25
DE69735384T2 (de) 2006-08-10
ES2158611T3 (es) 2001-09-01
US6130200A (en) 2000-10-10
EP0959873A2 (fr) 1999-12-01
PT959873E (pt) 2006-07-31
NZ335851A (en) 2001-02-23
JP2010120952A (ja) 2010-06-03
ES2256898T3 (es) 2006-07-16
WO1998027962A3 (fr) 1998-10-01
WO1998027962A2 (fr) 1998-07-02
CA2591581C (fr) 2013-01-29
AU5615498A (en) 1998-07-17
AU739469B2 (en) 2001-10-11

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